The invention relates to formulations of cyclosporin with high bioavailability for oral administration, which contain about 1 part by weight of one or more cyclosporin(s), preferably cyclosporin A and/or cyclosporin G, 7.5 to 7.8 parts by weight of one or more polyethylene glycol esters of saturated C10-C22hydroxy fatty acids, 0.7 to 0.85 part by weight of a monohydric alcohol as co-solvent, and 0.7 to 0.8 part by weight of a polyhydric alcohol as co-solvent. The drug form is produced by initially dissolving the cyclosporin in ethanol and, while stirring, adding propylene glycol and SOLUTOL(copyright) HS 15 until a clear, viscous solution results, bottled as drinkable solution or packed into capsules.

The invention relates to cyclosporin, especially cyclosporin A, containing liquid formulations and soft gelatin capsules for oral administration.
Cyclosporins are neutral cyclic peptides produced by microbes. The most important representative of the cyclosporins is cyclosporin A, which is used in transplant therapy for suppressing organ rejection and in bone marrow transplantation.
Cyclosporin A, its microbiological production, and its isolation and purification to an amorphous, colorless powder is disclosed per se in German Patent 2,455,859.
Cyclosporin A is increasingly also being used in the treatment of autoimmune diseases such as psoriasis, uveitis, nephrotic syndrome and others.
Antiinflammatory and antiparasitic properties are described for the cyclosporins.
Because of the hydrophobic nature of cyclosporin, it is difficult to produce pharmaceutical compositions resulting in high bioavailability of the active ingredient, and there is a very wide inter- and intra-individual variability in the pharmacokinetic parameters. At the same dose, the cyclosporin level in the blood varies by up to 50% from patient to patient. Absorption varies widely even in one and the same patient. However, immunosuppressive therapy relies on a very narrow therapeutic window between dose-dependent side effects and rejection of the transplanted organ.
Poor bioavailabilities are attributable in particular to the low solubility of cyclosporin in the mixture of cyclosporins in dosage forms containing water.
There have thus been very numerous attempts to solve these pharmaceutical problems.
Known and commercially available dosage forms accordingly employ complicated systems of lipophilic and hydrophilic solvents and solubilizing detergents, with the aim of dissolving cyclosporins and keeping them in solution in aqueous systems. They consist of at least four ingredients: namely, active ingredient, vege-table oil, ethanol, and a surfactant.
U.S. Pat. No. 4,388,307 discloses the use of oil and ethanol as vehicle in conjunction with co-solvents. Based on this patent, commercially available drinkable solutions of cyclosporin contain olive oil, ethanol and, as surface-active substance, Labrafil(copyright). This formula entails problems, however. Oils and surface-active vehicles often have an unpleasant odor and/or taste. In addition, oils with unsaturated fatty acids are prone to rancidity.
Secondly, a relatively high content of ethanol is necessary in formulas containing oils. However, this high ethanol content entails difficulties on administration of the products to children and results in storage problems.
When used for filling capsules it is necessary, for the purpose of preventing evaporation, to increase the elaboration of finishing by packaging in aluminium blister packs.
Newer dosage forms disclosed in GB Patent 2,222,770 comprise routes to solutions by the production of micro-emulsions. These systems consist of 4 to 6 components which form a complicated system of active ingredient, lipophilic, hydrophilic phase, and a surface-active substance. Systems of this type entail an increased risk of cross-reaction and the risk that one of the substances used is not tolerated by the patient.
German Patent 3,924,207 discloses a process for producing stable aqueous injection solutions for intravenous administration, which can be administered orally, in which
a) 1 part by weight of cyclosporin
b) 8-13 parts by weight of one or more monoesters of a or of saturated hydroxy fatty acids with polyethylene glycol and
c) 1-13 parts by weight of one or more mono- and/or polyhydric alcohols are mixed.
Pharmaceutical forms which can be used orally have not been produced and investigated in this patent. On attempting to produce formulations in the lower concentration ranges, stated by the inventors, of one or more mono- or polyhydric alcohols, no solution which can provide clear dilutions with water, which is essential for good bioavailability of the active ingredient, is obtained.
All commercially obtainable dosage forms contain oily, lipophilic ingredients (corn oil, kernel oil, corn oil mono-, di-, triglycerides) and one or more detergents and mono- or polyhydric alcohols.
It is evident from DE-A 3,843,054 that orthorhombic crystalline forms such as CY-A/X-II and, in particular, CY-A/X-III are particularly suitable for producing pharmaceutical forms. These formulations are said to contain cyclosporin in stable and fine-particle form and/or have better stability or more favorable release characteristics. These forms are preferably for topical dermal or topical ophthalmic use. The process described for producing the solvate-free orthorhombic crystal forms using ultrasound is difficult to implement on the industrial scale.
It is likewise shown that cyclosporin in amorphous form is less suitable for producing dosage forms.
The problems which have been described have been solved according to the invention by the surprising finding that in cyclosporin dosage forms for oral administration with a simple composition and high bioavailability in the form of drinkable solution or capsules containing:
a) 1.0 part by weight of one or more amorphous cyclosporin(s) as active ingredient;
b) 7.5 to 7.8, preferably 7.7, parts by weight of one or more polyethylene glycol monoesters of saturated C10 to C22 hydroxy fatty acids, preferably SOLUTOL(copyright) HS 15;
c) 0.7 to 0.85, preferably 0.75, part by weight of a monohydric alcohol as co-solvent, preferably ethanol; and
d) 0.7 to 0.8, preferably 0.75, part by weight of a polyhydric alcohol as co-solvent, preferably propylene glycol
the cyclosporin(s) provide clear solutions, especially in dilutions with water, when these specific ratios of amounts are maintained.
With the selection of this specific solvent composition of a plurality of mono- and polyhydric alcohols in conjunction with the use of amorphous cyclosporin, a formulation which can provide clear dilutions with water in all ratios, especially at high concentrations of cyclosporin in the dosage form, has been found.
This was not normally to be assumed because the concentrations of the co-solvent stated in German Patent 3,924,207 does not permit stable aqueous solutions to be produced in the lower concentration range. Only the combination of mono- and polyhydric alcohols in the stated ratio makes it possible to produce solutions which have a high cyclosporin content and which afford solutions which can provide clear dilutions with water. It is furthermore essential for the possibility of providing clear dilutions with water that the ratio of the monohydric alcohol to the polyethylene glycol monoester is maintained and that the formula contains both mono- and polyhydric alcohols.
It was, therefore, all the more surprising that such a formula showed a bioequivalence with commercial products (see above).
In particular, it was not predictable that such a simple formula without lipophilic component could achieve such high bioavailabilities.
It has furthermore been found that precisely the use of amorphous cyclosporin in an oral administration form results in particularly good solution properties in formulas with a cyclosporin content  greater than 5%, which are also maintained in dilutions with water as stable, clear solution.
The invention, therefore, relates to oral dosage forms which, as drinkable solution or packed in capsules, contain the following ingredients in the following ratios of amounts:
a) 1.0 part by weight of one or more amorphous cyclosporin(s) as active ingredient;
b) 7.5 to 7.8, preferably 7.7, parts by weight of one or more polyethylene glycol monoesters of saturated C10 to C22 hydroxy fatty acids, preferably SOLUTOL(copyright) HS 15;
c) 0.7 to 0.85, preferably 0.75, part by weight of a monohydric alcohol as co-solvent, preferably ethanol; and
d) 0.7 to 0.8, preferably 0.75, part by weight of a polyhydric alcohol as co-solvent, preferably propylene glycol.
In the production process, which is likewise according to the invention, care must be taken that the ratios of amounts are maintained and that the cyclosporin is initially completely dissolved in ethanol with continuous stirring at room temperature and subsequently, likewise with continuous stirring and at room temperature, propylene glycol and Solutol(copyright) HS 15 are added. The solutions produced by this process contain 100 mg/mL active ingredient.
Finishing as drinkable solution or capsules takes place in a known manner, for example in capsules each containing 190 mg, 50 mg, or 25 mg of active ingredient.

Cyclosporin compositions and process therefor


According to embodiments of present disclosure, a method to produce a compound of Formula 19 is provided. Using this method, the compound of Formula 19 may be produced effectively.

Lipoxins are a series of anti-inflammatory mediators. Lipoxins are short lived endogenously produced nonclassic eicosanoids whose appearance in inflammation signals the resolution of inflammation. They are abbreviated as LX, an acronym for lipoxygenase (LO) interaction products. At present two lipoxins have been identified; lipoxin A4 (LXA4) and lipoxin B4 (LXB4).
Lipoxins were first described by Serhan, Hamberg and Samuelsson in 1984. They reported that the lipoxins stimulated superoxide anion (O2−) generation and degranulation at submicromolar concentrations—as potent as LTB4.
Lipoxins, as well as certain peptides, are high affinity ligands for the lipoxin A4 receptor (LXA4R), which was first identified based on sequence homology as the formyl peptide receptor like receptor (FPRL1). Lipoxin signaling through the LXA4R inhibits chemotaxis, transmigration, superoxide generation and NF-κB activation. Conversely, peptide signaling through the same receptor, in vitro, has been shown to stimulate chemotaxis of polymorphonuclear cells (PMNs) and calcium mobilization. The peptides that have ALXR affinity tend to be signals for leukocyte migration and subsequent phagocytosis such as acute phase proteins, bacterial peptides, HIV envelope proteins and neurotoxic peptides. Similarly to the leukotrienes, LXA4 will form the cysteinyl-lipoxins LXC4, LXD4 and LXE4. At subnanomolar concentrations, LXA4 and LXB4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. Lipoxins are high affinity antagonists to the cysteinyl leukotriene receptor type 1 (CysLT1) to which several leukotrienes (LTC4, LTD4 and LTE4) mediate their smooth muscle contraction and eosinophil chemotactic effects. The CysLT1 receptor is also the site of action for the asthma drug montelukast.

Synthesis of new anti-inflammatory compound


A medicinal aerosol formulation including 0.01-5% medicament, at least 50% by weight 1,1,1,2-tetrafluoroethane (134a), less than 5% surface active agent, and at least one compound having higher polarity than 1,1,1,2-tetrafluoroethane, and which is free of chlorofluorocarbons and propellants CHClF2, CH2F2 and CF3CH3.

This invention relates to medicinal aerosol formulations and in particular to formulations suitable for pulmonary, nasal, buccal or topical administration which are at least substantially free of chlorofluorocarbons.
Since the metered dose pressurised inhaler was introduced in the mid 1950""s, inhalation has become the most widely used route for delivering bronchodilator drugs and steroids to the airways of asthmatic patients. Compared with oral administration of bronchodilators, inhalation offers a rapid onset of action and a low instance of systemic side effects. More recently, inhalation from a pressurised inhaler has been a route selected for the administration of other drugs, e.g., ergotamine, which are not primarily concerned with treatment of a bronchial malady.
The metered dose inhaler is dependent upon the propulsive force of a propellant system used in its manufacture. The propellant generally comprises a mixture of liquified chlorofluorocarbons (CFC""s) which are selected to provide the desired vapour pressure and stability of the formulation, Propellants 11, 12 and 114 are the most widely used propellants in aerosol formulations for inhalation administration.
In recent years it has been established that CFC""s react with the ozone layer around the earth and contribute towards its depletion. There has been considerable pressure around the world to reduce substantially the use of CFC""s, and various Governments have banned the xe2x80x9cnon-essentialxe2x80x9d use of CFC""s. Such xe2x80x9cnon-essentialxe2x80x9d uses include the use of CFC""s as refrigerants and blowing agents, but heretofore the use of CFC""s in medicines, which contributes to less than 1% of the total use of CFC""s, has not been restricted. Nevertheless, in view of the adverse effect of CFC""s on the ozone layer it is desirable to seek alternative propellant systems which are suitable for use in inhalation aerosols.
U.S. Patent No. 4,174,295 discloses aerosol propellant compositions which consist of a mixture of a hydrogen-containing chlorofluorocarbon or fluorocarbon (A), selected from the group consisting of CHClF2 (Freon 22), CH2F2 (Freon 32) and CF3-CH3 (Freon 143a), with a hydrogen-containing fluorocarbon or chlorofluorocarbon (B) selected from the group consisting of: CH2ClF (Freon 31), CClF2-CHClF (Freon 123a), CF3-CHClF (Freon 124), CHF2-CClF2 (Freon 124a), CHClF-CHF2 (Freon 133), CF3-CH2Cl (Freon 133a), CHF2-CHF2 (Freon 134), CF3-CH2F (Freon 134a), CClF2-CH3 (Freon 142b) and CHF2-CH3 (Freon 152a). The compositions may contain a third component (C) consisting of a saturated hydrocarbon propellant, e.g., n-butane, isobutane, pentane and isopentanes. The propellant compositions comprise 5 to 60% of (A), 5 to 95% of (B) and 0 to 50% of (C) and are said to be suitable for application in the fields of: hair lacquers, anti-perspiration products, perfumes, deodorants for rooms, paints, insecticides, for home cleaning products, for waxes, etc. The compositions may contain dispersing agents and solvents, e.g., methylene chloride, ethanol etc.
It has now been found that 1,1,1,2-tetrafluoroethane has particularly suitable properties for use as a propellant for medicinal aerosol formulations when used in combination with a surface active agent and an adjuvant having a higher polarity than 1,1,1,2-tetrafluoroethane.
According to the present invention there is provided an aerosol formulation comprising a medicament, a surfactant, 1,1,1,2-tetrafluoroethane and at least one compound having a higher polarity than 1,1,1,2-tetrafluoroethane.
It has been found that 1,1,1,2-tetrafluoroethane, hereinafter referred to as Propellant 134a, may be employed as a propellant for aerosol formulations suitable for inhalation therapy when used in combination with a compound (hereinafter an xe2x80x9cadjuvantxe2x80x9d) having a higher polarity than Propellant 134a. The adjuvant should be miscible with Propellant 134a in the amounts employed. Suitable adjuvants include alcohols such as ethyl alcohol, isopropyl alcohol, propylene glycol, hydrocarbons such as propane, butane, isobutane, pentane, isopentane, neopentane, and other propellants such as those commonly referred to as Propellants 11, 12, 114, 113, 142b, 152a 124, and dimethyl ether. The combination of one or more of such adjuvants with Propellant 134a provides a propellant system which has comparable properties to those of propellant systems based on CFC""s, allowing use of known surfactants and additives in the pharmaceutical formulations and conventional valve components. This is particularly advantageous since the toxicity and use of such compounds in metered dose inhalers for drug delivery to the human lung is well established. Preferred adjuvants are liquids or gases at room temperature (22xc2x0 C.) at atmospheric pressure.
Recently it has been established that certain CFC""S which have been used as anesthetics are not significantly ozone depleting agents as they are broken down in the lower atmosphere. Such compounds have a higher polarity than Propellant 134a and may be employed in the composition of the invention. Examples of such compounds include 2-bromo-2-chloro-1,1,1,-trifluoroethane, 2-chloro-1-(difluoromethoxy)-1,1,2-trifluoroethane and 2-chloro-2-(difluoromethoxy)-1,1,1-trifluoroethane.
In contrast to the prior art the compositions of the invention do not require the presence of Freon 22, Freon 32 or Freon 143a to provide useful properties; these propellants are preferably absent or present in minor amounts of less than 5% by weight of the propellant composition. The compositions are preferably free from CFC""s.
The particular adjuvant(s) used and the concentration of the adjuvant(s) is selected according to the particular medicament used and the desired physical properties of the formulation.
It has been found that the use of Propellant 134a and drug asia binary mixture or in combination with a conventional surfactant such as sorbitan trioleate does not provide formulations having suitable properties for use with pressurised inhalers. It has been established that the physical parameters of polarity, vapour pressure, density, viscosity and interfacial tension are all important in obtaining a stable aerosol formulation, and by a suitable selection of a compound having a polarity higher than that of Propellant 134a stable aerosol formulations using Propellant 134a may be prepared.
The addition of a compound of higher polarity than Propellant 134a to Propellant 134a provides a mixture in which increased amounts of surfactant may be dissolved compared to their solubility in Propellant 134a alone. The presence of increased amounts of solubilised surfactant allows the preparation of stable, homogenous suspensions of drug particles. The presence of large amounts of solubilised surfactant may also assist in obtaining stable solution formulations of certain drugs.
The polarity of Propellant 134a and of an adjuvant may be quantified, and thus compared, in terms of a dielectric constant, or by using Maxwell""s equation to relate dielectric constant to the square of the refractive indexxe2x80x94the refractive index of materials being readily measurable or obtainable from the literature.
Alternatively, the polarity of adjuvants may be measured using the Kauri-butanol value for estimation of solvent power. The protocol is described in ASTM Standard: Designation 1133-86. However, the scope of the aforementioned test method is limited to hydrocarbon solvents having a boiling point over 40xc2x0 C. The method has been modified as described below for application to more volatile substances such as is required for propellant.
Standardisation
In conventional testing the Kauri resin solution is standardised against toluene, which has an assigned value of 105, and a mixture of 75% n-heptane and 25% toluene by volume which has an assigned value of 40. When the sample has a Kauri-butanol value lower than 40, it is more appropriate to use a single reference standard of 75% n-heptane:25% toluene. The concentration of Kauri-butanol solution is adjusted until a titre between 35 ml and 45 ml of the reference standard is obtained using the method of the ASTM standard.
Method for Volatile Compounds
The density of the volatile substance under test is calculated to allow a volumetric titration from the added weight of the sample after testing.
Kauri-butanol solution (20 g) is weighed into an aerosol bottle. A non-metering valve is crimped onto the bottle and the weight of bottle and sample measured. Following the procedure detailed in ASTM standards as closely as possible, successive amounts of the volatile sample are transferred from an aerosol bottle via a transfer button until the end point is reached (as defined in ASTM). The aerosol bottle with titrated Kauri-butanol solution is re-weighed.
The Kauri-butanol value is calculated using the following formula:   V  =                    (                              W            2                    -                      W            1                          )            d        xc3x97          40      B
in which:
W2 =weight of aerosol bottle after titration (g)
W1 =weight of aerosol bottle before titration (g)
d=density of sample (g/ml)
B is as defined in the ASTM standard and=ml of heptane-toluene blend required to titrate 20 g of Kauri-butanol solution.
If a titre (V) is obtained by precipitation of the Kauri resin out of solution, then a higher Kauri-butanol valve represents a sample of higher polarity.
If the sample and Kauri-butanol solution are immiscible, this is most likely to be due to the immiscibility of the sample with butanol resulting from an excessively low polarity. However, it is feasible that excessively high polarity could result in immiscibility. This is tested by checking the miscibility of the sample with water. If the sample is immiscible with water and immiscible with Kauri-butanol solution, then the Kauri-butanol value is deemed too low to be measured, and the polarity is to be regarded as lower than that of any material which would give a proper titre into Kauri-butanol solution.
The particular selection of adjuvant and concentration preferably provides the resulting mixture with a solubility parameter of from 6.0 to 8.5 (cal/cm3)xc2xd. A propellant system having a solubility parameter below 6.0 (cal/cm3)xc2xd is a door solvent for surfactants, resulting in unstable suspension formulations of drug. The preferred solubility parameter for the propellant system comprising Propellant 134a and adjuvant is in the range 6.5 to 7.8 (cal/cm3)xc2xd.
The vapour pressure of a propellant system is an important factor as it provides the propulsive force for the medicament. The adjuvant is selected to moderate the vapour pressure of Propellant 134a so that it is within the desired range. This allows for advantages in the manufacture of the dosage form and gives greater flexibility to obtain and vary the target vapour pressure at room temperature. Another factor in the choice of the adjuvant is that, whilst it should allow moderation of the vapour pressure of Propellant 134a, it should not easily demix when the mixture is cooled to lower temperatures for the purposes of manufacture of the aerosol formulation and filling the containers.
The vapour pressure may also be increased if desired depending on the choice of the adjuvant. It has been found that some of the propellant mixtures deviate from Raoult""s Law. The addition of certain alcohols makes very little change to the vapour pressure of the mixture with Propellant 134a at room temperature. However addition of certain hydrocarbons having a lower vapour pressure than Propellant 134a can result in a mixture having a higher vapour pressure.
The vapour pressure of the formulations at 25xc2x0 C. is generally in the range 20 to 150 psig (1.4 to 10.3xc3x97105 N/m2) preferably in the range 40 to 90 psig (2.8 to 6.2xc3x97105 N/m2).
The selection of adjuvant may also be used to modify the density of the formulation. Suitable control of the density may reduce the propensity for either sedimentation or xe2x80x9ccreamingxe2x80x9d of the dispersed drug powders. The density of the formulations is generally in the range 0.5 to 2.0 g/cm3, preferably in the range 0.8 to 1.8 g/cm3, more preferably in the range 1.0 to 1.5 g/cm3.
The selection of adjuvant may also be used to adjust the viscosity of the formulation which is desirably less than 10 cP.
The selection of adjuvant may also be used to adjust the interfacial tension of the propellant system. In order to optimise dispersion of drug particles and stability the interfacial tension of the formulation is desirably below 70 dynes/cm.
Propellant 134a is generally present in the aerosol formulations in an amount of at least 50% by weight of the formulation, normally 60 to 95% by weight of the formulation.
Propellant 134a and the component of higher polarity are generally employed in the weight ratio 50:50 to 99:1 Propellant 134a:high polarity component, preferably in the weight ratio 70:30 to 98:2 and more preferably in the weight ratio 85:15 to 95:5 Propellant 134a:high polarity component. Preferred compounds of higher polarity than Propellant 134a include ethanol, pentane, isopentane and neopentane.
The aerosol formulations comprise a surface active agent to stabilise the formulation and lubricate the valve components. Suitable surface active agents include both non-fluorinated surfactants and fluorinated surfactants known in the art and disclosed, for example, in British Patent Nos. 837465 and 994734 and U.S. Pat. No. 4,352,789. Examples of suitable surfactants include: oils derived from natural sources, such as, corn oil, olive oil, cotton seed oil and sunflower seed oil.
Sorbitan trioleate available under the trade name Span 85,
Sorbitan mono-oleate available under the trade name Span 80,
Sorbitan monolaurate available under the trade name Span 20,
Polyoxyethylene (20) sorbitan monolaurate available under the trade name Tween 20,
Polyoxyethylene (20) sorbitan mono-oleate available under the trade name Tween 80,
lecithins derived from natural sources such as those available under the trade name Epikuron particularly Epikuron 200.
Oleyl polyoxyethylene (2) ether available under the trade name Brij 92,
Stearyl polyoxyethylene (2) available under the trade name Brij 72,
Lauryl polyoxyethylene (4) ether available under the trade name Brij 30,
Oleyl polyoxyethylene (2) ether available under the trade name Genapol 0-020,
Block copolymers of oxyethylene and oxypropylene available under the trade name Synperonic,
Oleic acid, Synthetic lecithin, Diethylene glycol dioleate, Tetrahydrofurfuryl oleate, Ethyl oleate, Isopropyl myristate, Glyceryl trioleate, Glyceryl monolaurate, Glyceryl mono-oleate, Glyceryl monostearate, Glyceryl monoricinoleate, Cetyl alcohol, Stearyl alcohol, Polyethylene glycol 400, Cetyl pyridinium chloride.
The surface active agents are generally present in amounts not exceeding 5 percent by weight of the total formulation. They will usually be present in the weight ratio 1:100 to 10:1 surface active agent:drug(s), but the surface active agent may exceed this weight ratio in cases where the drug concentration in the formulation is very low.
Suitable solid medicaments include antiallergics, analgesics, bronchodilators, antihistamines,therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, anti-inflammatory preparations, hormones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, an alkaloid, or a steroid, and synergistic combinations of these. Examples of medicaments which may be employed are: Isoproterenol [alpha-(isopropylaminomethyl) protocatechuyl alcohol], phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, salbutamol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine. Others are antibiotics, such as neomycin, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline; adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, hydrocortisone, hydrocortisone acetate and prednisolone; insulin, antiallergy compounds such as cromolyn sodium, etc.
The drugs exemplified above may be used as either the free base or as one or more salts known to the art. The choice of free base or salt will be influenced by the physical stability of the drug in the formulation. For example, it has been shown that the free base of salbutamol exhibits a greater dispersion stability than salbutamol sulphate in the formulations of the invention.
The following salts of the drugs mentioned above may be used;
acetate, benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, and triethiodide.
Cationic salts may also be used. Suitable cationic salts include the alkali metals, e.g. sodium and potassium, and ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, e.g. glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol-amino-2-(hydroxymethyl)propane-1,3-diol and 1-(3,4-dihydroxyphenyl)-2 isopropylaminoethanol.
For pharmaceutical purposes the particle size of the powder should desirably be no greater than 100 microns diameter, since larger particles may clog the valve or orifice of the container. Preferably the particle size should be less than 25 microns in diameter. Desirably the particle size of the finely-divided solid powder should for physiological reasons be less than 25 microns and preferably less than about 10 microns in diameter. The particle size of the powder for inhalation therapy should preferably be in the range 2 to 10 microns.
There is no lower limit on particle size except that imposed by the use to which the aerosol produced is to be put. Where the powder is a solid medicament, the lower limit of particle size is that which will be readily absorbed and retained on or in body tissues. When particles of less than about one-half micron in diameter are administered by inhalation they tend to be exhaled by the patient.
The concentration of medicament depends upon the desired dosage but is generally in the range 0.01 to 5% by weight.
The formulation of the invention may be filled into conventional aerosol containers equipped with metering valves and dispensed in an identical manner to formulations employing CFC""s.

CRC-free medicinal aerosol formulations of 1,1,1,2-tetrafluoroethane (134A) with polar adjuvant


Unitary void-maintaining geocomposites, and drainage systems utilizing those geocomposites, are provided for location below a road surface or below a large structure such as a building, retaining wall or parking lot. In some embodiments, the geocomposites include at least one fluid-transmissible layer, preferably a geotextile, attached adjacent an upper or lower surface, or both surfaces, of a polymer-based core element. In other embodiments, the core element is constructed such that no geotextile layer is needed. Characteristic of the core element is high transmissivity, that is, a high rate of horizontal flow of gases or liquids through the core. Characteristic of the at least one fluid-transmissible layer is high permittivity, that is, a high rate of vertical transmission of liquids and gases through the geotextile layer and into the core element. Also characteristic of fluid-transmissible layers of the invention is high exclusivity with respect to solid materials. Core elements and fluid-transmissible layers can be formed simultaneously as a unit, or the several components may be bonded to one another by welding or adhesives. The systems include further drain means that communicate with the geocomposite structures of the system, such as perforated pipes and the like, which can connect further to culverts, ditches or waterways. The geocomposite structures and drain means may be placed below the subgrade, over the subgrade, or at the top and bottom of the base underlying a roadway or large structure. Unitary void-maintaining geocomposites can form part of a greater subsurface geosynthetic system that provides reinforcement, separation, and drainage for the structure to thereby extend its useful life and decrease maintenance costs.

The present invention relates generally to void-maintaining geosynthetic systems for the drainage of water and other fluids, and more particularly to geosynthetic structures having a void-maintaining core that may be sandwiched between attached or uni-formed geotextile layers. Geosynthetic structures of the invention are ideal for providing subsurface drainage for roadways and other large structures such as parking lots, retaining walls and buildings.
The building of large structures such as roadways, buildings, parking lots, retaining walls, embankments and the like often involves the excavation, re-contouring and other movement of large quantities of earthen materials such as soil, rock, earth, gravel, sand and the like. Most large structures have underlying foundations of some sort to support the weight of the structure and thereby stabilize the structure in its desired position with respect to the earth and with respect to other parts of the same structure. For example, roadways and parking lots usually have foundations comprising a base aggregate immediately under the paved surface, and a subgrade layer under the base aggregate which supports the weight of both of the overlying structures. Commonly, both the base and subgrade are formed of stones, soil and other earthen materials and subjected repeatedly to grading, tamping or other compaction operations and thereby formed into a foundation of desired density, elevation, inclination and direction. Buildings commonly have concrete foundations or concrete slabs that support the weight of the overlying structure.
The presence of water or other fluids near, within or under such foundations can be quite disadvantageous. For example, water or other fluids in the foundation materials underlying such structures can cause hydraulic pore pressure buildup and reduction in the effective stress in the soil materials. These conditions can directly or indirectly contribute to failure of the underlying materials that support the overlying foundation and can thereby also cause a failure of the overlying structure. It is thus important to positively control the water or other fluids and dissipate pore pressure underlying large structures and in the vicinity of and underlying the foundations of such large structures.
The movement of soil particles around and underlying structures is not limited to that caused by the presence of fluids. Movement can occur from repeated or repetitive dynamic loads, as well as static loads that cause destabilizing stresses within the soil structure. One way of controlling such movement is to provide reinforcing products such as frameworks which are integral to the materials underlying the foundation, or within it, to thereby prevent or impede such undesired movement. Geosynthetics are materials often used to provide such a framework. The use of geosynthetics contributes to controlling movement of soil particles and structural fill materials in four primary ways:
1) By creating higher degrees of friction between the natural materials and the surface of the geosynthetic when compared to the frictional characteristics of the soil itself in order to minimize soil movement in horizontal, vertical and diagonal directions.
2) By confining soil fill material within the geosynthetic structure in an attempt to control lateral movement of soil particles.
3) By providing a nonporous, impermeable membrane type barrier that minimizes vertical migration of soil particles and fluids. At times, horizontal and diagonal movement of soil particles is impeded by roughening or texturing the geosynthetic in order to increase the friction between the soil and the geosynthetic.
4) By providing a semiporous, porous, or permeable barrier that minimizes vertical migration of soil particles by not allowing soil particles to move through openings in the geosynthetic that are effectively smaller than the diameter of the soil particles themselves, while also allowing fluids to migrate vertically, diagonally and horizontally irrespective of gravity through one or more layers of a single or multi-ply geosynthetic.
These porous, semiporporous or permeable geosynthetics allow fluids to pass vertically and horizontally through their structures. Capillary connections sometimes occur and are one aspect that allow fluids to migrate vertically and diagonally irrespective of gravity through multi-ply geosynthetics. Capillary connections are created by the contacting of two or more plys of geosynthetics and provide continuous vertical or diagonal capillary paths through which fluids may travel. Typically, capillary connections may appear in a semi-continuous pattern across the horizontal plane of a geosynthetic comprising more than one ply. These connections, which are formed when the polymer strands of one ply of a geosynthetic contact the polymer strands of another ply often occur when layers of geosynthetics are arranged or constructed to allow one ply to be placed directly on top of another ply. Polymer strands of individual geosynthetic plys assist fluid migration in the horizontal plane of the specific geosynthetic ply. This horizontal transmission of fluid can be expressed as a rate of flow per unit width within the plane of a geosynthetic and is typically called xe2x80x9ctransmissivity.xe2x80x9d On the other hand, the vertical transmission rate of fluid, or xe2x80x9cpermittivityxe2x80x9d of a geosynthetic is typically expressed by measuring the rate of flow per unit area per unit thickness. Permitivity is a quantifiable property that can be controlled during the maufacturering process.
Vertical and diagonal capillary connections can be created even when two or more plys of geosynthetic are arranged in substantially but parallel planes when polymer strands of one ply become in contact with the polymer strands of another ply. This can occur under the normal pressures that are placed upon the geosynthetic from the overlying soil burden which forces polymeric strands of the separate plys together thereby allowing fluids to migrate against gravity at the sites of the continuous capillary connections. The flow of fluids through a geosynthetic against gravity is often referred to as xe2x80x9cwicking,xe2x80x9d and is distinguished from permitivity. Wicking occurs after field installation of the product and is not a predictably quantifiable characteristic of the system but is dependent on a number of different factors. Wicking, the fluid transmission against gravity resulting from capillary connections created by the deformation and intercontact of geosynethic plys, is a property that is sometimes advantageous and other times disadvantageous.For example, in applications where the user desires water to be transmitted against gravity these, capillary connections may provide a benefit. In contrast, using geosynthetics in applications where the user does not want fluid to pass via the mechanism provided by the capillary connection can be a detriment to the particular structure.
In general, geosynthetics are manufactured as substantially planar, or sheetlike, products from polymeric materials. Geosynthetics are usually made in large scale, for example, several meters in width and many meters in length so that they are easily adaptable to large scale construction and landscaping uses. Some geosynthetics are flexible or fabric-like and therefore conform easily to uneven or rolling surfaces. Some geosynthetics are manufactured to be less flexible but to possess great tensile strength and resistance to stretching or great resistance to compression. Certain types of geosynthetic materials are used to reinforce large man-made structures, particularly those made of earthen materials such as gravel, sand and soil. In such uses, one purpose of using the geosynthetic is that of holding the earthen components together by providing a latticework or meshwork whose elements have a high resistence to stretching. By positioning the geosynthetic integral to the gravel, sand and soil, that is, with the gravel, sand and soil within the interstices of the geosynthetic, unwanted movement of the earthen components is minimized or eliminated. Most geosynthetic materials, whether of the latticework type or of the fabric type, allow water to pass through them to some extent and into the material within which the geosynthetic is integrally positioned. Thus, geosynthetic materials and related geotechnical engineering materials are used as integral parts of man-made structures or systems in order to stabilize their salient dimensions.
A particular problem faced by the FHWA, the DOT and many highway and transportation agencies across the United States and elsewhere is the high-cost and difficult maintenance of state and interstate roadways. A significant cause of this high cost and these difficulties is the entrapment and retention of water and other fluids which damage roadways and greatly reduce their useful life. This is the case even on those projects where conventional geosynthetics are used. Water in pavement systems that are inclusive or exclusive of geosynthetic is one of the principal causes of pavement distress. Fluid such as water enters the subsurface either from the subgrade soil, that is, the native ground upon which the roadway is constructed, or from rainwater or floodwater penetrating open spaces such as cracks and pits within the road surface. Under common usage, vehicular traffic across the roadway produces a dynamic or repetitious loading force on the road that creates a xe2x80x9cpumping actionxe2x80x9d that draws fluid through the subgrade into the subbase or base coarse of the road. When this fluid is retained within the subbase or road base, damage to the roadway occurs. As indicated in the AASHTO design methodology (1993), drainage performance can range from excellent (water is removed from the roadway systems within two hours) to poor drainage (water is removed within one month). The corresponding drainage coefficient (direct design parameter) for an excellent drainage is 3.0 times greater then the corresponding drainage coefficient for poor drainage. The higher drainage coefficient increases the structural number. Therefore, the service life of the structures can be extended or the overall structural cross-section can be reduced. When there is a high fluid content within the soil supporting the traffic lanes, reduced bearing capacity can occur, resulting in deformation of the contour of the road, wheel rutting, and premature collapse or failure of the roadway.
Another drainage issue particular to construction of roadways and other large structures in regions with cold climates relates to frost damage to pavements due to frost heaving and subsequent thawing. Frost heaving, the raising of the pavement surface occurs due to the formation of ice lenses, which can grow up to several centimeters in the thickness, in the underlying soil. Differential frost heaving leads to adverse pavement roughness and hazardous driving conditions. Thawing or frozen pavements in frost-melting periods causes a supersaturated soil condition. If the drainage provisions are inadequate, the bearing capacity of the pavement is substantially reduced, which in turn causes bearing capacity failure or surface cracking. Traffic loading during the thaw season can also pump fine-grained subgrade soils into the subbase or base course. Among the economic losses by frost damage are costs of repair and maintenance, possible restrictions of vehicle weight-limits or even complete closure of the traffic. All of these conditions can be extremely costly. To reduce damage caused by frost heaving, in 1963 the U.S. Army Corps of Engineers suggested two strategies: 1)the control of surface deformation resulting from frost action by limiting the amount of frost-susceptible soil subjected to freezing temperatures; and 2) employing designs of adequately large bearing capacities sufficient to withstand stresses experienced during the most critical climatic period. This means a significant increase in aggregate thickness and the concomitant increase in cost and time required to construct a given structure.
Design methods based on the above two concepts call for the use of clean, nonfrost-susceptible base material. Such material is becoming more and more expensive to obtain and transport. Due to the required serviceability that an engineer must account for in the design for their clients, these types of expensive soils are often forced to be considered in civil engineering projects, thus making demand for them higher and, consequently, an increase in their prices.
Frost damage can be reduced by introducing a capillary break, or water barrier, to reduce water migration into the freezing front. Various methods are known to deal with this problem. For example, Finland and Sweden have used a layer or sand to break the capillary connection between frost-susceptible soils (Rengmark, 1963; Taivenen, 1963). This insulating layer of sand was found to help reduce and smooth frost heave, and also to increase the bearing capacity during the spring thaw.
Before the present invention, previous drainage systems using geosynthetic structures are exclusively limited to providing drainage at the edge or shoulder of a roadway. These edge-drain systems are commonly located within a covered trench originally dug along the shoulder of the roadway, in an area which receives little or no dynamic load from the roadway. Usually serving a dual purpose, the edge-drain relies upon natural drainage from directly beneath the road surface within the subbase or subgrade to carry fluid to the edge-drains for collection and further distribution, for example, by way of a shoulder pipe. The material of the subbase or subgrade acts also as a filter to prevent adjacent soil from clogging the drainage system. The drainage system directly beneath the surface of a roadway is often made of unstabilized granular, asphalt stabilized granular, or cement stabilized aggregate material. Such xe2x80x9cnatural materialxe2x80x9d drainage systems, if installed properly, can be used to carry large amounts of fluid from the subbase to the edge-drain.
There are many disadvantages to natural material drainage systems, however. Such systems require the subsurface aggregate to possess a uniform size gradation to provide void spaces, that is, interconnecting holes within the drainable base to carry fluid. Disadvantageously, the requirement for interconnecting void spaces to afford good drainage conflicts with road pavement systems designed for long-term use. This is so because roadways designed for long-term use require minimal void spaces in order to reduce the movement of particles, sand and aggregate. Free-draining aggregate usually require an asphaltic or cement stabilize binder to facilitate construction. Additionally, a well-graded granular or geotextile filter layer is needed to prevent contamination of the open graded base through the migration of subgrade fines. This extra filter layer further increases the cost of the roadway construction. Furthermore, high construction costs are incurred for a complete drainage layer of natural stone or sand that must be installed with precision, and extensive on-site quality control must be exercised, in order to produce a high-flow draining system which lasts for the life of the overlying paved surface.
When positioned directly beneath the road surface, conventional geosynthetic structures are primarily used to provide reinforcement of the base, subgrade stabilization, subgrade restraint, separation of the base course from the subgrade, or as a thermal break to provide insulation from temperature changes. Until the present invention, however, geosynthetic materials had not been designed or implemented to provide a positive drainage system effective enough to provide adequate drainage for an entire roadway or for an entire roadway portion. Similarly, until the present invention, no geosynthetic material had ever been designed to break the capillary connection that can occur as a result of the repeated dynamic traffic loads that can cause a capillary connection between different plys of geosynthetics, nor has a geosynthetic ever been used to provide a void maintaining system for the entire design life of a roadway and thereby serve as an effective capillary break to prevent moisture migration into the base course layer or into the frost susceptible soil layer, or underneath an entire roadway.
There is therefore a need for a drainage system that can be positioned within a large structure and provide efficient and cost-effective drainage for the structure while also providing a capillary break by utilizing components which can be engineered and manufactured offsite.
The present invention overcomes the previously mentioned disadvantages by providing a drainage system which provides interconnected drainage voids and also functions as a capillary break under substantial portions of the ground underlying roadways, parking lots, retaining walls, buildings and other large structures. Structures of the present invention are unitary void-maintaining geocomposite structures (to be sold under the trademark xe2x80x9cUVMGxe2x80x9d) UVMG""s according to the invention can be constructed and positioned within one or more of the subsurface levels at predetermined locations under a large structure such as a roadway or building. The present UVMG""s typically comprise a void-maintaining core such as a geonet adjacent to one or more layers of fluid-transmissable geotextile fabric. The structures are unitary in that the core element is preferably manufactured simultaneously with its filtration medium to form a unitary geocomposite. Another method of manufacture is for the core element and geotextile elements to be formed separately and then adhered to one another by heat, laser or electron beam welding, or by means of adhesives applied to one or more of the components to thereby form a unitary structure in advance of installation of the UVMG at a desired site.
The permittivity of a material relates to its ability to permit gases, water and other fluids to pass vertically, or substantially vertically, through the material. The fluid-transmissible layers of the present invention provide high permittivity of subsurface fluids such as water into the core element. Geotextiles are preferred as the fluid-transmissible layers of the invention. Other materials possessing high permittivity and high occlusiveness to solids are also suitable for the present invention. Structures of the present invention also possess high transmissivity. The transmissivity of a material relates to its ability to transmit gases, water or other fluids horizontally, or substantially horizontally, in a particular or desired direction. Typically, permittivity is measured as the rate of flow per unit area per unit width while transmissivity is measured in terms of rate of flow per unit width. Core elements of the present invention possess high transmissivity because of their interconnecting openings, which permit fluids to flow substantially horizontally away from the overlying or underlying structure. Thus, UVMG""s eliminate many of the problems presented by the presence or movement of fluids such as water in the areas underlying large structures. By eliminating these problems, the useful life of the subject structure is extended.
The present invention relates generally to unitary void-maintaining geocomposite structures and systems for water drainage, and more particularly to such geocomposite structures combined with additional drainage elements such as pipes, conduits, edge drains, culverts and ditches for the subsurface drainage of roadways and other large structures such as parking lots, retaining walls and buildings.
A principal object of the present UVMG invention is to provide a subsurface drainage system that, among other things, provides a capillary break to thereby prevent unwanted movement of the structure, such as frost heaving, to thereby extend the useful life of a roadway or other large structure.
It is another object of the present invention to provide cost-effective alternatives to previous large-structure subsurface drainage systems.
An additional object of the invention is to provide unitary geocomposite materials which include both void-maintaining elements and geotextile or other filtration elements having high permitivity for fluids while preventing solid particles that are larger than openings in the filtration element from entering the void-maintaining system.
It is a further object of the present invention to transfer certain quality control aspects of road construction and reconstruction from the construction site to a manufacturing facility for roadway drainage products.
It is yet another object of the present invention to provide subsurface drainage unitary void-maintaining geocomposites as part of a greater road subsurface geosysthentic system to thereby enable efficient reinforcement, separation, filtration, gas transmission and egress, and drainage for a large structure such as a roadway, retaining wall, parking lot or building.
In accordance with this and other objects, the present invention provides a drainage system for draining fluids away from a roadway or other large structure, comprising a unitary void-maintaining geocomposite, the geocomposite comprising a geocomposite core element having a plurality of interconnected voids, the core element having an upper surface and a lower surface, and at least one fluid-transmissible layer of high permittivity adjacent the upper surface, wherein the layers are constructed and arranged so that the geocomposite maintains voids of sufficient dimension that the water from the roadway or other large structure can move freely through the geocomposite, and wherein the geocomposite is sloped downwardly from the roadway or other large structure.
The unitary void maintaining geocomposite may further comprise at least one fluid-transmissible layer, for example, a geotextile, adjacent the lower surface of the void-maintaining geocomposite, and may also further comprise drain means adjacent the void-maintaining geocomposite and communicating therewith such that the fluid can move from the void-maintaining geocomposite to the drain means, wherein the drain means is sloped preferably downwardly from the void-maintaining geocomposite. In accordance with advantageous drainage aspects of the invention the void-maintaining geocomposite is sloped downwardly away from a portion of the roadway or the large structure such that the fluid is directed away from the roadway or the large structure and the void-maintaining geocomposite communicates with the drain means under the roadway or at a margin of the roadway or the large structure.
In accordance with additional objects of the invention, the drain means may further comprise a ditch or culvert adjacent a margin of the roadway or the large structure, and the drainage means may comprise perforated piping such as is commonly found in civil engineering applications.
In some preferred embodiments of the present invention, the void-maintaining geocomposite wraps around the circumference of the perforated piping and the perforated piping is connected to further drains means wherein the further drain means is one or more selected from the group consisting of non-perforated pipes, drainage ditches, sumps, canals, streams and rivers. Preferably one or both of the geotextile layers are attached to the geocomposite core element by heat or fusion welding, by laser welding, or by adhesives known in the geotextile arts. Of course, as one of skill in the art can appreciate, in certain applications, it may be most efficacious to position the geotextile layers adjacent the geocomposite core element without attaching them to one another. This may be preferable in situations where separate portions of geocomposite core element are overlapped or butt joined to one another and where it is desirable that no similar joint exists in the corresponding geotextile layer.
In other preferred embodiments of the invention the geocomposite core element comprises a geonet such as that found in U.S. Pat. No. 5,891,549 to Beretta et al. In other preferred embodiments, the geocomposite core element is tri-planar such as shown in U.S. Pat. No. 5,255,998 and comprises polyethlene, polypropylene or other polymer derivatives, and both fluid-transmissible layers are geotextiles that are nonwoven and needle punched. U.S. Pat. Nos. 5,891,549 and 5,255,998 are incorporated herein by reference.
In accordance with additional advantageous aspects of the invention, the void-maintaining geocomposite structure is constructed and arranged to form a wrapping adjacent to and around the circumference of the perforated piping such that a portion of one of the upper or lower fluid-transmissible geotextile layers is removed along the length of the wrapping so that the geocomposite core contacts the piping and the removed portion of the one of the upper or lower fluid-transmissible geotextile layers is overlapping and connected to the other surface fluid-transmissible geotextile layer. As one of skill in the art will recognize, it is advantageous to provide piping or other drain means which has a capacity to carry away a sufficient volume of fluid collected through the relatively large surface area of the present geocomposite core element.
Moreover, by interconnecting the various portions of the present invention such that the various interconnecting voids maintain flow paths for fluid such as water entering the system, large areas under highways, buildings, parking lots, and other large structures can be effectively drained without the necessity of complex and expensive structures. In order to maintain the interconnections preferred in the present invention, the overlapping portions of the fluid-transmissible geotextile layers are connected by ties, welding or by sewing, and the portions of the fluid-transmissible geotextile layers and the geocomposite core element of the void-maintaining geocomposite are held adjacent to the piping by circumferential ties around the geocomposite. Of course, as one of skill will recognize, the present invention is particularly advantageous for draining water-containing fluids or other geologic fluids such as petroleum or natural gas from roadways and other large structures.
In accordance with other aspects of the present invention, a drainage system disposed at a level below the top surface of a roadway for draining fluids such as water away from the roadway is provided, wherein the system comprises a unitary void-maintaining geocomposite comprising a geocomposite core element having a plurality of interconnected voids, the core element having an upper surface and a lower surface, and at least one fluid-transmissible geotextile layer of high permittivity attached adjacent the upper surface, wherein the layers are constructed and arranged so that the unitary void-maintaining geocomposite structure maintains voids of sufficient dimension that the water from the roadway can move freely through the geocomposite, and wherein the geocomposite is sloped downwardly from the top surface of the roadway.
Unitary void maintaining composites further comprise at least one fluid-transmissible layer, preferably a geotextile, attached adjacent the lower surface of the core element and, preferably, drain means adjacent the geocomposites and communicating therewith such that the fluid can move from the geocomposites to the drain means, wherein the drain means is sloped downwardly from the geocomposites such that the fluid is directed away from the roadway, wherein the geocomposite is constructed and arranged to provide a capillary break between the roadway pavement system and the earthen materials under the geocomposite.
In accordance with still other aspects of the present invention, the unitary void-maintaining geocomposites of the present invention can be positioned in a roadway to maximize their effectiveness. For example, in order to provide positive drainage functions, as needed, the geocomposite can be positioned intermittently or continuously below the top Portland Cement Concrete (xe2x80x9cPCCxe2x80x9d) or asphalt layer of the roadway. To provide a capillary break in frost-prone regions, the geocomposite can be placed between the underground water table and frost-penetration depth, or freezing front. The present geocomposites can also be used to provide a capillary break function in non-frost-prone regions where the base layer contains fine grained soil with the potential for vented moisture migration through capillary rising. In order to maximize other advantages of the present invention, the void-maintaining geocomposites may be positioned in multiple layers, and at various levels below the roadway surface in order to maximize drainage efficiency as desired.
The void-maintaining geocomposites of the present invention can be made in large pieces, for example, in pieces several meters wide and many meters long. For convenience and installation, however, the geocomposites of the present invention, or their components can be installed in portions which are interconnected such that the interconnecting voids are of sufficient dimension that the water from the roadway can move freely through the geocomposite and can be connected to drain means such as a ditch or culvert adjacent a margin of the roadway or the large structure or perforated piping.
Moreover, the void-maintaining geocomposites of the present invention can be constructed and arranged to prevent wicking upward, to provide continuous or discontinuous capillary breaks across the area of the geocomposite, or to prevent wicking substantially altogether by the provision of void spaces.
Other advantages of the present invention are found in the methods which it provides. The present invention includes methods for providing drainage systems for roadways or other large structures. For example, the present invention provides a method for constructing a drainage system for draining fluids away from a roadway or other large structure, the method comprising providing a void-maintaining geocomposite including at least one geocomposite core element having a plurality of interconnected voids, the core element having an upper surface and a lower surface, and at least one fluid-transmissible geotextile layer adjacent the upper surface, wherein the components are constructed and arranged so that the geocomposite maintains voids of sufficient dimension that the water from the roadway or other large structure can move freely through the geocomposite, and wherein the geocomposite is sloped downwardly from the roadway or other large structure.
Preferably, the void-maintaining geocomposite further comprises at least one fluid-transmissible geotextile layer of high transmissivity adjacent the lower surface of the geocomposite and drain means adjacent the geocomposite and communicating therewith such that the fluid can move from the geocomposite to the drain means, wherein the drain means is sloped downwardly from geocomposite.
The high transmissivity layers and core elements of the void-maintaining geocomposites of the invention can be positioned at junctions between pieces such that high transmissivity between the void spaces maintained within the geocomposite and those of the drain means is maintained. With respect to the joining of large pieces of the geocomposites, this can be accomplished, for example, by providing geotextile layers which extend beyond the margins of the core composite layer, or by positioning additional pieces of geotextile over the joint areas. With respect to the junctions between the drain means and the geocomposites, portions of the geotextiles can be positioned around the drain means to thereby decrease the likelihood of the intrusion of clogging materials and to maintain the connection between voids of the geocomposites and those of the drain means.
The means and methods of the present invention include the positioning of the geocomposites and drain means in many permutations depending on the particular needs of the structure to be drained. For example, geocomposites of the invention can be positioned below the roadway or large structure and above an aggregate layer if desired. Moreover, the present methods include combinations wherein the geocomposite is positioned below the roadway or large structure in portions which are interconnected such that the interconnecting voids are of sufficient dimension that the water from the roadway can move freely through the connecting portions and thereby through the geocomposite. The present methods include wherein the drain means further comprises a ditch or culvert adjacent a margin of the roadway or the large structure.
As a further advantage, the combinations and methods of the invention comprise wherein the roadway base course comprises materials which have been excavated from the subgrade of the roadway and wherein the roadway base course comprises materials which have been excavated from the subgrade of the roadway and mixed with imported materials.

Drainage system with unitary void-maintaining geosynthetic structure and method for constructing system


The present invention provides plating solutions, particularly metal plating solutions, designed to provide uniform coatings on substrates and to provide substantially defect free filling of small features, e.g., micron scale features and smaller, formed on substrates with none or low supporting electrolyte, i.e., which include no acid, low acid, no base, or no conducting salts, and/or high metal ion, e.g., copper, concentration. Additionally, the plating solutions may contain small amounts of additives which enhance the plated film quality and performance by serving as brighteners, levelers, surfactants, grain refiners, stress reducers, etc.

1. Field of the Invention
This application claims priority from U.S. Provisional application Ser. No. 60/082,521, filed Apr. 21, 1998. The present invention relates to new formulations of metal plating solutions designed to provide uniform coatings on substrates and to provide defect free filling of small features, e.g., micron scale features and smaller, formed on substrates.
2. Background of the Related Art
Electrodeposition of metals has recently been identified as a promising deposition technique in the manufacture of integrated circuits and flat panel displays. As a result, much effort is being focused in this area to design hardware and chemistry to achieve high quality films on substrates which are uniform across the area of the substrate and which can fill or conform to very small features.
Typically, the chemistry, i.e., the chemical formulations and conditions, used in conventional plating cells is designed to provide acceptable plating results when used in many different cell designs, on different plated parts and in numerous different applications. Cells which are not specifically designed to provide highly uniform current density (and the deposit thickness distribution) on specific plated parts require high conductivity solutions to be utilized to provide high xe2x80x9cthrowing powerxe2x80x9d (also referred to as high Wagner number) so that good coverage is achieved on all surfaces of the plated object. Typically, a supporting electrolyte, such as an acid or a base, or occasionally a conducting salt, is added to the plating solution to provide the high ionic conductivity to the plating solution necessary to achieve high xe2x80x9cthrowing powerxe2x80x9d. The supporting electrolyte does not participate in the electrode reactions, but is required in order to provide conformal coverage of the plating material over the surface of the object because it reduces the resistivity within the electrolyte, the higher resistivity that otherwise occurs being the cause of the non-uniformity in the current density. Even the addition of a small amount, e.g., 0.2 Molar, of an acid or a base will typically increase the electrolyte conductivity quite significantly (e.g., double the conductivity).
However, on objects such as semiconductor substrates that are resistive, e.g., metal seeded wafers, high conductivity of the plating solution negatively affects the uniformity of the deposited film. This is commonly referred to as the terminal effect and is described in a paper by Oscar Lanzi and Uziel Landau, xe2x80x9cTerminal Effect at a Resistive Electrode Under Tafel Kineticsxe2x80x9d, J. Electrochem. Soc. Vol. 137, No. 4 pp. 1139-1143, April 1990, which is incorporated herein by reference. This effect is due to the fact that the current is fed from contacts along the circumference of the part and must distribute itself across a resistive substrate. If the electrolyte conductivity is high, such as in the case where excess supporting electrolyte is present, it will be preferential for the current to pass into the solution within a narrow region close to the contact points rather than distribute itself evenly across the resistive surface, i.e., it will follow the most conductive path from terminal to solution. As a result, the deposit will be thicker close to the contact points. Therefore, a uniform deposition profile over the surface area of a resistive substrate is difficult to achieve.
Another problem encountered with conventional plating solutions is that the deposition process on small features is controlled by mass transport (diffusion) of the reactants to the feature and by the kinetics of the electrolytic reaction instead of by the magnitude of the electric field as is common on large features. In other words, the replenishment rate at which plating ions are provided to the surface of the object can limit the plating rate, irrespective of current. Essentially, if the current density dictates a plating rate that exceeds the local ion replenishment rate, the replenishment rate dictates the plating rate. Hence, highly conductive electrolyte solutions that provide conventional xe2x80x9cthrowing powerxe2x80x9d have little significance in obtaining good coverage and fill within very small features. In order to obtain good quality deposition, one must have high mass-transport rates and low depletion of the reactant concentration near or within the small features. However, in the presence of excess acid or base supporting electrolyte, (even a relatively small excess) the transport rates are diminished by approximately one half (or the concentration depletion is about doubled for the same current density). This will cause a reduction in the quality of the deposit and may lead to fill defects, particularly on small features.
It has been learned that diffusion is of significant importance in conformal plating and filling of small features. Diffusion of the metal ion to be plated is directly related to the concentration of the plated metal ion in the solution. A higher metal ion concentration results in a higher rate of diffusion of the metal into small features and in a higher metal ion concentration within the depletion layer (boundary layer) at the cathode surface, hence faster and better quality deposition may be achieved. In conventional plating applications, the maximum concentration of the metal ion achievable is typically limited by the solubility of its salt. If the supporting electrolyte, e.g., acid, base, or salt, contain a co-ion which provides a limited solubility product with the plated metal ion, the addition of a supporting electrolyte will limit the maximum achievable concentration of the metal ion. This phenomenon is called the common ion effect. For example, in copper plating applications, when it is desired to keep the concentration of copper ions very high, the addition of sulfuric acid will actually diminish the maximum possible concentration of copper ions. The common ion effect essentially requires that in a concentrated copper sulfate electrolyte, as the sulfuric acid (HS2O4) concentration increases (which gives rise to H+ cations and HSO4xe2x88x92 and SO4xe2x88x92 anions), the concentration of the copper (II) cations decreases due to the greater concentration of the other anions. Consequently, conventional plating solutions, which typically contain excess sulfuric acid, are limited in their maximal copper concentration and, hence, their ability to fill small features at high rates and without defects is limited.
Therefore, there is a need for new formulations of metal plating solutions designed particularly to provide good quality plating of small features, e.g., micron scale and smaller features, on substrates and to provide uniform coating and defect-free fill of such small features.
The present invention provides plating solutions with none or low supporting electrolyte, i.e., which include no acid, low acid, no base, or no conducting salts, and/or high metal ion, e.g., copper, concentration. Additionally, the plating solutions may contain small amounts of additives which enhance the plated film quality and performance by serving as brighteners, levelers, surfactants, grain refiners, stress reducers, etc.
The present invention generally relates to electroplating solutions having low conductivity, particularly those solutions containing no supporting electrolyte or low concentration of supporting electrolyte, i.e., essentially no acid or low acid (and where applicable, no or low base) concentration, essentially no or low conducting salts and high metal concentration to achieve good deposit uniformity across a resistive substrate and to provide good fill within very small features such as micron and sub-micron sized features and smaller. Additionally, additives are proposed which improve leveling, brightening and other properties of the resultant metal plated on substrates when used in electroplating solutions with no or low supporting electrolyte, e.g., no or low acid. The invention is described below in reference to plating of copper on substrates in the electronic industry. However, it is to be understood that low conductivity electroplating solutions, particularly those having low or complete absence of supporting electrolyte, can be used to deposit other metals on resistive substrates and has application in any field where plating can be used to advantage.
In one embodiment of the invention, aqueous copper plating solutions are employed which are comprised of copper sulfate, preferably from about 200 to about 350 grams per liter (g/l) of copper sulfate pentahydrate in water (H2O), and essentially no added sulfuric acid. The copper concentration is preferably greater than about 0.8 Molar.
In addition to copper sulfate, the invention contemplates copper salts other than copper sulfate, such as copper fluoborate, copper gluconate, copper sulfamate, copper sulfonate, copper pyrophosphate, copper chloride, copper cyanide and the like, all without (or with little) supporting electrolyte. Some of these copper salts offer higher solubility than copper sulfate and therefore may be advantageous.
The conventional copper plating electrolyte includes a relatively high sulfuric acid concentration (from about 45 g, of H2SO4 per L of H2O (0.45M) to about 110 g/L (1.12M)) which is provided to the solution to provide high conductivity to the electrolyte. The high conductivity is necessary to reduce the non-uniformity in the deposit thickness caused by the cell configuration and the differently shaped parts encountered in conventional electroplating cells. However, the present invention is directed primarily towards applications where the cell configuration has been specifically designed to provide a relatively uniform deposit thickness distribution on given parts. However, the substrate is resistive and imparts thickness non-uniformity to the deposited layer. Thus, among the causes of non-uniform plating, the resistive substrate effect may dominate and a highly conductive electrolyte, containing, e.g., high H2SO4 concentrations, is unnecessary. In fact, a highly conductive electrolyte (e.g., generated by a high sulfuric acid concentration) is detrimental to uniform plating because the resistive substrate effects are amplified by a highly conductive electrolyte. This is the consequence of the fact that the degree of uniformity of the current distribution, and the corresponding deposit thickness, is dependent on the ratio of the resistance to current flow within the electrolyte to the resistance of the substrate. The higher this ratio is, the lesser is the terminal effect and the more uniform is the deposit thickness distribution. Therefore, when uniformity is a primary concern, it is desirable to have a high resistance within the electrolyte. Since the electrolyte resistance is given by 1/xcexaxcfx80r2, it is advantageous to have as low a conductivity, xcexa, as possible, and also a large gap, 1, between the anode and the cathode. Also, clearly, as the substrate radius, r, becomes larger, such as when scaling up from 200 mm wafers to 300 mm wafers, the terminal effect will be much more severe (e.g., by a factor of 2.25). By eliminating the acid, the conductivity of the copper plating electrolyte typically drops from about 0.5 S/cm (0.5 ohmxe2x88x921 cmxe2x88x921) to about {fraction (1/10)} of this value, i.e., to about 0.05 S/cm, making the electrolyte ten times more resistive.
Also, a lower supporting electrolyte concentration (e.g., sulfuric acid concentration in copper plating) often permits the use of a higher metal ion (e.g., copper sulfate) concentration due to elimination of the common ion effect as explained above. Furthermore, in systems where a soluble copper anode is used, a lower added acid concentration (or preferably no acid added at all) minimizes harmful corrosion and material stability problems. Additionally, a pure or relatively pure copper anode can be used in this arrangement. Because some copper dissolution typically occurs in an acidic environment, copper anodes that are being used in conventional copper plating typically contain phosphorous. The phosphorous forms a film on the anode that protects it from excessive dissolution, but phosphorous traces will be found in the plating solution and also may be incorporated as a contaminant in the deposit. In applications using plating solutions with no acidic supporting electrolytes as described herein, the phosphorous content in the anode may, if needed, be reduced or eliminated. Also, for environmental considerations and ease of handling the solution, a non acidic electrolyte is preferred.
Another method for enhancing thickness uniformity includes applying a periodic current reversal. For this reversal process, it may be advantageous to have a more resistive solution (i.e., no supporting electrolyte) since this serves to focus the dissolution current at the extended features that one would want to preferentially dissolve.
In some specific applications, it may be beneficial to introduce small amounts of acid, base or salts into the plating solution. Examples of such benefits may be some specific adsorption of ions that may improve specific deposits, complexation, pH adjustment, solubility enhancement or reduction and the like. The invention also contemplates the addition of such acids, bases or salts into the electrolyte in amounts up to about 0.4 M.
A plating solution having a high copper concentration (i.e.,  greater than 0.8M) is beneficial to overcome mass transport limitations that are encountered when plating small features. In particular, because micron scale features with high aspect ratios typically allow only minimal or no electrolyte flow therein, the ionic transport relies solely on diffusion to deposit metal into these small features. A high copper concentration, preferably about 0.85 molar (M) or greater, in the electrolyte enhances the diffusion process and reduces or eliminates the mass transport limitations. The metal concentration required for the plating process depends on factors such as temperature and the acid concentration of the electrolyte. A preferred metal concentration is from about 0.8 to about 1.2 M.
The plating solutions of the present invention are typically used at current densities ranging from about 10 mA/cm2 to about 60 mA/cm2. Current densities as high as 100 mA/cm2 and as low as 5 mA/cm2 can also be employed under appropriate conditions. In plating conditions where a pulsed current or periodic reverse current is used, current densities in the range of about 5 mA/cm2 to about 400 mA/cm2 can be used periodically.
The operating temperatures of the plating solutions may range from about 0xc2x0 C. to about 95xc2x0 C. Preferably, the solutions range in temperature from about 20xc2x0 C. to about 50xc2x0 C.
The plating solutions of the invention also preferably contain halide ions, such as chloride ions, bromide, fluoride, iodide, chlorate or perchlorate ions typically in amounts less than about 0.5 g/l. However, this invention also contemplates the use of copper plating solutions without chloride or other halide ions.
In addition to the constituents described above, the plating solutions may contain various additives that are introduced typically in small (ppm range) amounts. The additives typically improve the thickness distribution (levelers), the reflectivity of the plated film (brighteners), its grain size (grain refiners), stress (stress reducers), adhesion and wetting of the part by the plating solution (wetting agents) and other process and film properties. The invention also contemplates the use of additives to produce asymmetrical anodic transfer coefficient (xcex1a) and cathodic transfer coefficient (xcex1c) to enhance filling of the high aspect ratio features during a periodic reverse plating cycle.
The additives practiced in most of our formulations constitute small amounts (ppm level) from one or more of the following groups of chemicals:
1. Ethers and polyethers including polyalkylene glycols
2. Organic sulfur compounds and their corresponding salts and polyelectrolyte derivatives thereof.
3. Organic nitrogen compounds and their corresponding salts and polyelectrolyte derivatives thereof.
4. Polar heterocycles
5. A halide ion, e.g., Clxe2x88x92
Further understanding of the present invention will be had with reference to the following examples which are set forth herein for purposes of illustration but not limitation.